TREFOILS AND MUCOSAL REPAIR In 1989, Thim reported on a family of gastrointestinal peptides that had 6 half-cystine residues and formed 3 disulfide bonds.These included: 1. pS2 peptide; a 60 amino acid residue breast cancer associated protein which was isolated from human gastric juice and the culture media of the human breast cancer cell line, MCF-7. 2. PSP; a 106 amino acid residue pancreatic spasmolytic polypeptide (PSP) which was isolated from porcine pancreas and pancreatic juice. This protein has a growth factor stimulatory effect on MCF-7 cells. 3. A 49 and 50 amino acid residue peptide predicted from a cDNA isolated from the skin of the frog, Xenopus laevis. . Formation of disulfide bonds in these polypeptides created a characteristic 3-leaved structure which was designated as "Trefoil" meaning "three-leaves". The characteristics of this family are summarized below: Trefoil factor 1 (TFF1). A secretory protein expressed by goblet cells of small and large bowel and also in the uterus. Trefoil factor 3 (TFF3) This gene is linked to those encoding other known human trefoil peptides, the breast cancer estrogen-inducible gene and the spasmolytic protein-1 (pS2) Spasmolytic protein 1 (SML) . This secretory -protein which is found in stomach inhibits gastrointestinal motility and gastric acid secretion. It could function as a structural component of the gastric mucus by establishing glycoproteins in the mucus gel through interactions with the carbohydrate side chains. Playford et al hypothesized that human pS2 is important in stimulating mucosal repair. For testing this idea, they produced transgenic mice strain that expressed human pS2 (hpS2) specifically within the jejunum. Expression of hpS2 in these animals was confined to the enterocytes of the villi within the jejunum. In these animals, damage in the bowel by administration of indomethacin, produced a different picture in the control and the transgenic mice. In the nondamaged intestine, the height of the villi and crypt cell proliferation rate were similar in transgenic and negative (control) litter mates. However, in the damaged areas in the jejunum, there was 30% reduction in the villus height in controls whereas there was only 12% reduction in these parameters in the transgenic animals. The amount of damage in the non-hpS2-expressing ileal region was similar in control and transgenic animals. These studies suggested that trefoil peptides may have a role in gastrointestinal repair. In the Oct 11 issue of Science, Lefebvre et al reported on the knockout of the pS2 gene. The mpS2 null mice exhibited dysfunctionality and severe hyperplasia and dysplasia of the antral and pyloric areas of gastric mucosa. Ultimately, adenomas and in 30% of the homozygous animals, multifocal intraepithelial and intramucosal carcinomas developed. Mashimo et al also reported in the same issue of Science on the knockout of the gene of intestinal trefoil factor (ITF). Induction of damage in the gastrointestinal tract by the administration of dextran sulfate sodium to these mice showed that ITF deficient mice have impaired mucoal healing and poor epithelial regeneration. The mice died from extensive colitis. These findings showed that ITF is a factor that participates in the healing and repairing mechanisms in the intestinal mucosa. REFERENCES: Thim, L. : A new family of growth factor-like peptides: 'trefoil' disulphide loop structures as a common feature in breast cancer associated peptide (pS2), pancreatic spasmolytic polypeptide (PSP), and frog skin peptides (spasmolysins). FEBS Lett. 250: 85-90, 1989. MEDLINE UID : 89290040 Thim, L.; Woldike, H. F.; Nielsen, P. F.; Christensen, M.; Lynch-Devaney, K.; Podolsky, D. K. : 95234704 Chinery, R.; Williamson, J.; Poulsom, R. : Podolsky, D. K.; Lynch-Devaney, K.; Stow, J. L.; Oates, P.; Murgue, B.; DeBeaumont, M.; Sands, B. E.; Mahida, Y. R. : 93203271 Schmitt, H.; Wundrack, I.; Beck, S.; Gott, P.; Welter, C.; Shizuya, H.; Simon, M. I.; Blin, N. : 96218774 R. J. Playford, T. Marchbank, R. A. Goodlad, R. A. Chinery, R. Poulsom, A. M. Hanby, N. A. Wright: Transgenic mice that overexpress the human trefoil peptide pS2 have an increased resistance to intestinal damage. Proc Natl Acad Sci USA 93, 2137-2142, 1996 Olivier Lefebvre, Marie-Pierre Chenard, Régis Masson, José Linares, Andrée Dierich, Marianne LeMeur, Corinne Wendling, Catherine Tomasetto, Pierre Chambon, Marie-Christine Rio: Gastric Mucosa Abnormalities and Tumorigenesis in Mice Lacking the pS2 Trefoil Protein. Science 274, 259-262, 1996 Hiroshi Mashimo, Deng-Chyang Wu, Daniel K. Podolsky, Mark C. Fishman: Impaired Defense of Intestinal Mucosa in Mice Lacking Intestinal Trefoil Factor. Science 274, 262-265, 1996 RESOURCES: SCOP: Fold: Trefoil DATABASE LINKS: Gene Map Locus: 21q22.3 (TFF1)